<p>PAPA syndrome is a rare autosomal dominant autoinflammatory disorder characterized by sterile pyogenic arthritis, pyoderma gangrenosum (PG), and severe acne, driven by PSTPIP1 mutations that enhance IL-1β production. IL-1 inhibitors—anakinra and canakinumab—have been reported in small case series, but comparative effectiveness, safety, and optimal dosing remain unclear. A systematic review of ten original case-report studies (19 patients) was performed, following PRISMA guidelines. Data extracted included clinical manifestations, treatment regimens, therapeutic responses across arthritis, PG, and acne, and adverse events. Complete resolution of pyogenic arthritis occurred in 11/17 treatment courses, versus 3/11 for PG and 4/10 for acne. Partial improvements were noted in 2 arthritis, 4 PG, and 1 acne cases; non-responses were most frequent in PG (4/11) and acne (5/10). Canakinumab demonstrated improved patient compliance due to its less frequent dosing schedule (every 4–8 weeks), in contrast to daily injections of anakinra. This also correlated with a trend toward fewer injection-site reactions. Reported adverse events were primarily mild, including local reactions and occasional infections. Anti-IL-1 therapy appears most effective for arthritis manifestations in PAPA syndrome, with markedly lower efficacy for PG and acne. Canakinumab’s dosing schedule offers practical advantages and potentially fewer adverse effects, but existing evidence is limited to case reports and small series. Well-designed randomized controlled trials are urgently needed to confirm efficacy, safety, and comparative benefits of anakinra versus canakinumab. Future studies should also explore genotype–phenotype correlations and extend investigation to adjunctive pathways to improve cutaneous outcomes.</p>